Pronounced and sustained central hypernoradrenergic function in major depression with melancholic features: Relation to hypercortisolism and corticotropin-releasing hormone

Both stress-system activation and melancholic depression are characterized by fear, constricted affect, stereotyped thinking, and similar changes in a utonomic and neuroendocrine function. Because norepinephrine (NE) and corti cotropin-releasing hormone (CRH) can produce these physiological and behavi oral changes, we measured the cerebrospinal fluid (CSF) levels each hour fo r 30 consecutive hours in controls and in patients with melancholic depress ion. Plasma adrenocorticotropic hormone (ACTH) and cortisol levels were obt ained every 30 min. Depressed patients had significantly higher CSF NE and plasma cortisol levels that were increased around the clock. Diurnal variat ions in CSF NE and plasma cortisol levels were virtually superimposable and positively correlated with each other in both patients and controls. Despi te their hypercortisolism, depressed patients had normal levels of plasma A CTH and CSF CRH. However, plasma ACTH and CSF CRH levels in depressed patie nts were inappropriately high, considering the degree of their hypercortiso lism. In contrast to the significant negative correlation between plasma co rtisol and CSF CRH levels seen in controls, patients with depression showed no statistical relationship between these parameters. These data indicate that persistent stress-system dysfunction in melancholic depression is inde pendent of the conscious stress of the disorder. These data also suggest mu tually reinforcing bidirectional links between a central hypernoradrenergic state and the hyperfunctioning of specific central CRH pathways that each are driven and sustained by hypercortisolism. We postulate that alpha-norad renergic blockade, CRH antagonists, and treatment with antiglucocorticoids may act at different loci, alone or in combination, in the treatment of maj or depression with melancholic features.